Joint trauma as encountered during sports or other types of injury causes acute cartilage damage and joint inflammation and significantly increases long-term risk for the development of osteoarthritis (OA). After acute injury, patients experience severe and disabling joint pain and inflammation. Therapies that address the acute posttraumatic phase or prevent the development of chronic disabling OA are not available. Our previous research identified cartilage cell death as an important process after mechanical joint injury and in OA. Caspases are a class of enzymes that execute cell death and also activate interleukins that are important mediators of joint inflammation. In previous in vitro and animal model studies we established proof-of-concept that caspase inhibitors are effective in inhibiting cartilage cell death and in reducing the severity of experimental OA. The overall objective of the proposed project is to complete preclinical development of caspase inhibitors and enable a Phase I clinical trial in patients with joint trauma. We have access to a caspase inhibitor that has already been in clinical trials for liver disease. The formulation development (Aim 1) will demonstrate that the formulated caspase inhibitor is released in a biologically active form and has extended intraarticular retention time. The animal model studies (Aim 2) will test the formulated caspase inhibitor in comparison to the free drug and a vehicle control. Endpoints are quantitative measurements of cartilage degradation and joint inflammation. Biochemical markers will be included as secondary endpoints and correlated with the biomarkers observed in humans in Aim 4. Preclinical safety information and Phase II clinical safety data already exists on the caspase inhibitor. In aim 3 we will use standard assays that follow FDA guidance to establish safety of the formulated inhibitor following intraarticular injection. In parallel with these preclinical studies we will perform a clinical study (Aim 4) to characterize the patient population with posttraumatic arthritis to identify MRI and biochemical markers that predict and correlate with joint inflammation and cartilage degradation. Together, the preclinical and clinical components in this project will enable initiation of the first Phase I study to specifically address the needs for treatment of the acute symptoms and the prevention of chronic disability in humans with posttraumatic arthritis.